Download Cell Cycle Checkpoint

Cell Cycle Checkpoint
The cell cycle: cells duplicate their
contents and divide
The cell cycle may be divided into 4
phases
The cell cycle triggers essential
processes (DNA replication, mitosis)
Cell Cycle Checkpoints
Progression of the cell cycle is regulated by
feedback from intracellular events
Major
Checkpoint Monitoring Molecules
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Cyclins
Cyclin Dependent Kinases (CDKs)
p53 - DNA damage
RB - Retinoblastoma
APC - Anaphase Promotin Complex
Cyclin-dependent protein kinases drive
progression through the cell cycle
• Cyclin-dependent kinases (Cdks)
are inactive unless bound to
cyclins
• Active complex phosphorylates
downstream targets
• Cyclin helps to direct Cdks to the
target proteins
Cellular levels of (mitotic) M-cyclin
rises and falls during the cell cycle
• M-cyclin levels are low during interphase but gradually
increases to a peak level during mitosis
• M-cdk activity is, likewise, low in interphase but increases
in mitosis
The abundance of cyclins (and the
activity of Cdks) is regulated by protein
degradation
• M-cyclin becomes covalently modified by addition of multiple copies of
ubiquitin at the end of mitosis
• Ubiqutination is mediated by the anaphase promoting complex (APC)
• Ubiquitination marks cyclins for destruction by large proteolytic machines
called proteasome
Cdks are also regulated by cycles of
phosphorylation and dephosphorylation
Cdk activates itself indirectly via a
positive feedback loop
Distinct cyclins partner with distinct Cdks
to trigger different events of the cell cycle
S-Cdk triggers DNA replication - its
destruction ensures this happens once per
cell cycle
Checkpoints ensure the cell cycle
proceeds without errors
Checkpoint: DNA damage arrests
the cell cycle in G1
Checkpoint: spindle assembly
• Mitosis must not complete unless all the
chromosomes are attached to the mitotic spindle
• Mitotic checkpoint delays metaphase to anaphase
transition until all chromosomes are attached
• Prolonged activation of the checkpoint -->cell
death
• Mechanism of many anti-cancer drugs
Cells can withdraw from the cell
cycle and dismantle the regulatory
machinery
• G0 is a quiescent state
• Cdks and cyclins disappear
• Some cells enter G0 temporarily and divide
infrequenty (I.e. hepatocytes)
• Other differentiated cell types (neurons) spend
their life in G0
p53 Anti-tumorigenic
• p53 suppresses cell
replication and growth
when there is DNA
damage.
• Impact of less that
diploid complement of
p53.
p53 Activity
Outcome of p53
Activation
• Halts cell cycle until
repair is completed.
• Launches cell into
apoptosis (programmed
cell death).
Loss of RB
– Enables continuous DNA
synthesis
– Defects in p16, cyclin D,
Cdk4 have same result
– Found in melanoma and
liposarcoma
Anaphase Promoting Complex (APC)
Checkpoint Failure
Cancer
• Normal cell division:
– Controlled by cell cycle checkpoints
• CHECKPOINTS – critical control points that determine
if a cell will move to the next portion of the cell cycle.
• Cancerous cell division:
– Ignores the cell cycle checkpoints
• Caused by DNA mutations
• Cells grow and divide out of control
• Cancerous cells do not perform designated purpose.
• Crowd out normal cells that do perform designated
purpose.
Cell Cycle Checkpoints
• G1/S
– Monitors cell size and for DNA damage
• G2/M
– Replication complete, DNA damage?
• M
– Spindle fibers connected, etc.?
• G0
– Does body require more of my type of cell?
Control of cell division continued:
Density Dependent Inhibition: Normal cells cease dividing once
critical cell density is reached. Cancer cells do not possess this trait.
Cancer is a disease of the cell cycle. Some of the
body’s cells divide uncontrollably and tumors form.
Tumor in Colon
Tumors in Liver
While normal cells will stop dividing if there is a mutation in the DNA,
cancer cells will continue to divide with mutation.
Due to DNA mutations, cancer cells ignore the chemical
signals that start and stop the cell cycle. They don’t
communicate with neighboring cells and continue to grow and
form tumors.